1. Field of the Invention
The invention relates to compounds which affect the relaxation time of atomic nuclei. More particularly, it pertains to compounds for use in effecting the relaxation times for nuclei in animal and human tissue which can be used for diagnosis through NMR imaging.
2. Description of the Prior Art
The NMR imaging method is based on the characteristic of certain atomic nuclei which have their own magnetic momentum and, in particular, protons, of orienting themselves, as the result of a magnetic field, in a state of equilibrium from which they can be moved by the use of pulses of a given radio frequency (resonance frequency).
The nuclei then return to their original state of equilibrium as a result of spin-spin and spin-lattice relaxation. The time required for returning to the state of equilibrium, known as relaxation time, gives valuable information on the degree of organization of the atoms and on their interaction with their environment.
On the basis of differences in proton density and relaxation times, images of biological tissues can be obtained which may be used for diagnostic purposes.
The greater the differences in the relaxation times of the nuclei which are present in the tissues being examined, the greater will be the contrast in the image that is obtained; cf., for example, P. Brunner et al, J. of Magnetic Resonance, 33, 83, 106 (1979).
It is known that the relaxation times of neighboring nuclei can be affected by the use of complex paramagnetic salts (G. C. Levy, et al, J. Amer. Chem. Soc. 96, 678-681 (1974)). It has therefore been proposed to administer paramagnetic ions to living organisms in order to improve the diagnostic information by the localized increase in relaxivity obtainable specifically by the use of paramagnetic substances: P. C. Lauterbur et al, Frontiers of Biol. Energetics Vol., I, 752-759 (1978); F. H. Doyle et al, Proc. of NMR Imaging Symp. held in Nashville, Tenn., U.S.A., on Oct. 26-27, 1980; J. A. Koutcher et al, J. of Nuclear Medicine 25:506-513 (1984). Various ions of transition metals and lanthanides are paramagnetic (F. A. Cotton et al., Advanced Inorganic Chemistry 1966, 634-639).
Specifically, paramagnetic ions which have a particularly strong effect on relaxation times are, for example, gadolinium.sup.(3+), iron.sup.(3+), manganese.sup.(2+), and chromium.sup.(3+) ; cf. G. L. Wolf et al., Magnetic Resonance Annual 1985 (Raven Press, New York), 231-266.
These ions of transition metals and lanthanides are, however, too toxic for use in man: R. J. Walker, R. William "Haemochromatosis and Iron Overload", in: Iron in Biochemistry and Medicine; A. Jacobs, M. Worwood, Eds., Academic Press, London, pp. 589-613 (1974); G. G. Cotzias, "Manganese in Health and Disease", Physiol. Rev. 38, 503-532 (1958); P. Arvela, "Toxicity of Rare Earths", Prog. Pharmacol. 2, 71-114 (1979).
We have therefore an incentive to deal with this problem by trying to reduce the toxic effect of metal ions administered for diagnostic purposes by combining these ions with suitable agents: F. Hosain et al, Radiology 91, 1199-1203 (1968), describe, for example, complex compounds of diethylene triaminopentacetate (DTPA) of the lanthanide ytterbium.
Gadolinium can also be successfully detoxified by combining it, for example, with diethylene triaminopentacetic acid; but this greatly reduces the relaxivity and, therefore, the contrast-reinforcing action compared to free Gd.sup.3+ (Weinmann et al., AJR 142:619-624 (1984).
Another problem is that the compound is not always less toxic than the free ion: in the same paper, for example, Weinmann et al. report that the toxicity of the ethylenediaminotetracetic compound (EDTA) of gadolinium is higher than that of gadolinium trichloride.
The specific usefulness and tolerance of metallic complexes must therefore be individually investigated in every single case.
Weinmann reports in Physiol. Chem. Phys. Med. NMR 1984, 16, 167-172 on the pharmacokinetics of the gadolinium-DTPA complex which indicates that this complex is distributed in the organism both in the vascular space and in the considerably larger interstitium. This is a disadvantage, for example, in the imaging of blood vessels, because it requires a much larger amount of contrast medium than would be needed in the case of a contrast medium whose distribution is limited to the vascular space. See, in this respect, M. Ogan et al., "Approaches to the Chemical Synthesis of Macromolecular NMR Imaging Contrast Media for Perfusion-Dependent Enhancement", presented at the 71st Scientific Assembly and Annual Meeting RSNA, Chicago, Nov. 17-22, 1985.
Media for NMR diagnosis which contain complex paramagnetic salts of the lanthanides and transition metals are given broad coverage in European patent EP-B 71,564. Equally extensive processes for NMR diagnosis by means of complexes of lanthanides are described in EP-A 135,125 (DuPont).
Schering's European Pat. No. 71 564 covers compounds of the types according to formulas I to IV: ##STR5## N-Hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA) ##STR6## N,N,N',N",N"-Diethylenetriaminepentaacetic acid (DTPA) EQU HOH.sub.2 C--CH.sub.2 N(CH.sub.2 COOH).sub.2 (III)
N-Hydroxyethyliminodiacetic acid ##STR7## wherein m represents 1 to 4
n represents 0 to 2 PA0 R' represents a saturated or unsaturated hydrocarbon group with 4 to 12 hydrocarbon atoms or the group --CH.sub.2 --COOH, PA0 R.sub.3 represents, alkyl of 1 to 4 carbon atoms, or the --CH.sub.2 --COOH group, and PA0 b is an integer from 0 to 4; Me.sup.(a+) is Fe.sup.(2+), Fe.sup.(3+), Gd.sup.(3+), or Mn.sup.(2+) ; PA0 E.sup.(b+) is an ion(s) of an alkali metal or alkaline earth metal, alkyl ammonium, alkanol ammonium, polyhydroxyalkyl ammonium, or basic protonated amino acid, with the ions representing a total charge of b units; PA0 m is an integer from 1 to 5; PA0 R PA0 R.sub.1 is the same as R.sub.2 or is --CH.sub.2 COOZ, --CH(CH.sub.3)COOZ, CH.sub.2 CH.sub.2 --N(CH.sub.2 COOZ).sub.2, a hydroxy arylalkyl, hydroxy pyridylalkyl, hydroxy aryl(carboxy)alkyl or hydroxy pyridyl-(carboxy)-alkyl radical, where the aryl or pyridyl radical may be substituted by hydroxyl, hydroxy alkyl, alkyl, halogen, carboxyl or SO.sub.3 H; PA0 is --CH.sub.2 COOZ, --CH(CH.sub.3)COOZ, ##STR10## where R.sub.3 is --CH.sub.2 COOZ, --CH(CH.sub.3)COOZ or a monovalent radial of the structure R--O--(CH.sub.2).sub.m --CH--COOZ; PA0 Z is hydrogen or a unit of negative charge, and --(CH.sub.2).sub.m -- may also be --CH.sub.2 --C(CH.sub.3).sub.2 --. PA0 Q represents .dbd.CH-- or .dbd.N--, PA0 A represents hydrogen, hydroxyl, lower hydroxy alkyl, and PA0 B represents hydrogen, lower alkyl, halogen, carboxyl or SO.sub.3 H. Fe.sup.(3+) is preferred as the metal ion. ##STR15## where a, b, Me.sup.(a+), E.sup.(b+), R, R.sub.1, R.sub.3, m, n, X and Z have the same meaning as set forth in general formula I. PA0 CA is --COOZ, --COOalkyl, --CONH.sub.2, --CONH--R'.sub.1,--CN: PA0 D is halogen (Cl, Br, I), --OSO.sub.2 alkyl/aryl, --OSO.sub.2 Oalkyl/aryl; PA0 R'.sub.1 is a protected group R.sub.1, easily transformable into --R.sub.1 by, for example, hydrolysis, hydrogenolysis, alkylation; PA0 R'.sub.2 is a protected group R.sub.2, easily transformable into --R.sub.2 ; PA0 R'.sub.3 is a protected group R.sub.3, easily transformable into --R.sub.3 ; PA0 X' is a protected group X, easily transformable into X. (The expression "easily transformable into" means simply that the protecting group can be easily removed by conventional means to produce the corresponding desired group.) PA0 R.sub.6 /R.sub.7 =H, alkyl (CH.sub.3); R.sub.6 +R.sub.7 also=--(CH.sub.2).sub.1-5 ;
or disphosphonic acids of the general formula V ##STR8## wherein R.sub.2 represents hydrogen, alkyl of 1 to 4 carbon atoms, halogen, the hydroxy-, amino- or CH.sub.2 --COOH groups and,
the ions of the lanthanide elements of numbers 57 to 70 or the ions of the transition metals of numbers 21 to 29, 42 and 44, and an organic base, by which as organic base glucamine, N-methylglucamine, N,N-dimethylglucamine, ethanolamine, diethanolamine, morpholine, lysine, ornithine and arginine are concerned, optionally with the usual additives in the art, dissolved or suspended in water or physiological salt solution characterized in that one brings into a form for oral or intravascular application, the paramagnetic complex salt dissolved or suspended in water or a physiological salt solution optionally with the usual additives in the art.
Complex compounds of iron.sup.(3+) and gadolinium.sup.(3+) for the imaging of the gastrointestinal tract are described in EP-A 124,766.
All agents proposed up to now for NMR diagnosis, which consists of complexes of heavy metals, are not very satisfactory with regard to their practical use in man or create more or less serious problems with regard to relaxivity and tolerance. Also, they frequently exhibit insufficient selectivity of the bond with the heavy metal, insufficient stability, and particularly, lack of selective targeting to certain organs.
The tendency of many complexes to exchange the central metal ion for trace metals which are essential to the organism or for ions, for example Ca.sup.(2+), which in vivo are present in relatively large amounts (cf., on this point, P. M. May, "The Present Status of Chelating Agents in Medicine", in: Progress in Medical Chemistry 20, 1983 (Elsevier Science Publ.) p. 233) ultimately limits their applicability, particularly in dosages which would be desirable for NMR diagnosis.
In the case of insufficient specific stability of the complex, trace metals of vital importance may, in fact, be extracted from the organism, and undesirable heavy metals, such as Gd may be deposited in their place which may remain in the organism for a long time.
Contrast media with organ specificity for NMR contrast imaging, which contain paramagnetic complexes of lanthanides, are being claimed in the published French patent application No. 2,550,449 and in EP-A 133,603. The solutions proposed there are, however, still limited and not optimal.
Therefore, there exists, now as before, a demand for contrast agents for the representation of the individual organs (for example, liver, bile ducts, spleen, pancreas, lymph nodes) and their respective anatomically pathological and functional changes.
Such paramagnetic substances for effective application in man should satisfy some or all of the following requirements:
1. A strong effect on the relaxation times T.sub.1 and T.sub.2 (particularly T.sub.1); in other words, they should induce a high level of relaxation which, by increasing the contrast in the image, makes it possible among other things to obtain relevant information in a short amount of time with obvious advantages in terms of the economic cost of each single examination, full utilization of equipment, etc.
2. A high level of stability of the complex, both in solution and in the organism. This means that the complexing agents exhibit a high level of selectivity for the relevant paramagnetic ions as opposed to the physiological ions.
3. A distribution which is specific to the organ and the tissue in the organism.
4. An elimination kinetics which is specific to the organ and the tissue.